TNX-102 SLAttribution is a small, rapidly-disintegrating sublingual (under-the-tongue) tablet containing 2.8 mg of cyclobenzaprine HCl for daily bedtime use. Tonix is developing TNX-102 SL at the 5.6 mg dose as a potential treatment for PTSD. In the AtEase Trial, TNX-102 SL 5.6 mg taken sublingually at bedtime demonstrated efficacy (reduction in CAPS-5 score) and safety for the treatment of military-related PTSD compared to placebo (see below). TNX-102 SL targets mechanisms which are associated with disturbed sleep and nightmares. It is believed that restoring deeper stages of sleep in PTSD may allow the body's natural recovery processes from severe trauma to be established, resulting in recovery from daytime symptoms of intrusion, pathological avoidance and agitation.
In December 2016, TNX-102 SL was granted Breakthrough Therapy designation by the FDA for the treatment of PTSD.
Sleep disturbances are core symptoms of PTSD. These disturbances are classified as 're-experiencing' symptoms when they manifest as distressing dreams and nightmares, and as 'hyperarousal' symptoms when insomnia or restless sleep are present. Poor sleep quality after a trauma is linked to the onset of PTSD and correlates with depression, substance abuse and suicide. As supported by prior clinical studiesFootnoteFootnote, TNX-102 SL may have the potential to improve disturbed sleep and provide relief to the symptoms experienced by people with PTSD. Research by Tonix has shown that TNX-102 SL acts on multiple neurotransmitter systems which relate to common sleep disturbances in PTSD:
The active ingredient of TNX-102 SL, cyclobenzaprine hydrochloride, has an extensive history of clinical use and is one of most widely-prescribed medications in the U.S. as an acute treatment for muscle spasm. As a sublingual, low-dose formulation for use at bedtime, TNX-102 SL is designed to optimize the delivery and absorption of cyclobenzaprine for the treatment of PTSD. As cyclobenzaprine products have been approved only for short-term use, TNX-102 SL is undergoing clinical development for long-term use.
Tonix announced topline results of the Phase 2 dose-finding clinical study of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in military-related PTSD (AtEase Study) on May 19, 2016.
The goal of the AtEase Study was to evaluate the potential clinical benefit of using TNX-102 SL to treat military-related PTSD at a dose of 2.8 mg or 5.6 mg. The AtEase Study identified the 5.6 mg dose as a clinically effective and well-tolerated dose for registration studies. TNX-102 SL 5.6 mg taken sublingually at bedtime demonstrated efficacy (reduction in CAPS-5 score) and safety for the treatment of military-related PTSD compared to placebo.
In a randomized, placebo-controlled study of 231 patients with PTSD at 25 U.S. clinical sites, a bedtime sublingual dose of 2.8 mg TNX-102 SL (n=90) or 5.6 mg TNX-102 SL (n=49) was compared to placebo (n=92) for the treatment of military-related PTSD. The retention rate was higher than typical for a PTSD clinical trial, since 73% completed the study on placebo, 79% on TNX-102 SL 2.8 mg and 84% on TNX-102 SL 5.6 mg. The primary efficacy endpoint was the 12-week mean change from baseline in the severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) between those treated with TNX-102 SL and those receiving placebo. The CAPS-5 is a standardized structured clinical interview and serves as the gold standard in research for measuring the symptom severity of PTSD.
This dose-finding study was designed to evaluate whether a 2.8 mg dose would be an efficacious dose and to provide an opportunity for this study to be one of the pivotal efficacy studies. Although the 2.8 mg dose trended in the direction of a therapeutic effect, it did not reach statistical significance on the primary endpoint. In contrast, the 5.6 mg dose had a therapeutic effect as assessed by the CAPS-5, which was statistically significant by analysis of covariance (ANCOVA) (p-value = 0.038), even though this arm of the study was designed to include half the number of patients of the 2.8 mg arm.
TNX-102 SL 2.8 mg and 5.6 mg were well tolerated as evidenced by the high overall completion rate in the active treatment groups, which exceeded the completion rate in the placebo group. The three treatment arms were well balanced on demographic characteristics. There were four distinct serious adverse events (SAEs); three were in the placebo group, and one (proctitis/peri-rectal abscess), in the TNX-102 SL group, was reported to be unrelated to TNX-102 SL.
Summaries of the preliminary efficacy and safety results are provided in the following tables:
Table 1. Preliminary Efficacy of TNX-102 SL in the AtEase Study
|2.8 mg (N=90)||5.6 mg (N=49)|
|CAPS-5||Total||MMRM1 with Multiple Imputation||0.211||0.031*|
|Arousal and Reactivity||MMRM||0.141||0.048*|
|Sleep E6 Item||MMRM||0.185||0.010*|
|Startle E4 Item||MMRM||0.336||0.015*|
|Sheehan Disability Scale||Total||MMRM||0.174||0.079|
|Family life/home responsibilities Item||MMRM||0.375||0.524|
1MMRM = Mixed Model Repeated Measures
2CGI-I = Clinician Global Impression-Improvement
3PGIC = Patient Global Impression of Change
*p < 0.05
Table 2. Preliminary Adverse Events Reported in > 5% of Subjects in Any Treatment Arm
|Placebo||2.8 mg||5.6 mg||Total TNX-102 SL|
|Local Administration Site Conditions|
|Hypoaesthesia oral||2 (2.1%)||36 (38.7%)||18 (36.0%)||54 (37.8%)|
|Paraesthesia oral||3 (3.2%)||15 (16.1%)||2 (4.0%)||17 (11.9%)|
|Glossodynia||1 (1.1%)||3 (3.2%)||3 (6.0%)||6 (4.2%)|
|Systemic Adverse Events|
|Somnolence||6 (6.4%)||11 (11.8%)||8 (16.0%)||19 (13.3%)|
|Dry mouth||10 (10.6%)||4 (4.3%)||8 (16.0%)||12 (8.4%)|
|Headache||4 (4.3%)||5 (5.4%)||6 (12.0%)||11 (7.7%)|
|Insomnia||8 (8.5%)||7 (7.5%)||3 (6.0%)||10 (7.0%)|
|Sedation||1 (1.1%)||2 (2.2%)||6 (12.0%)||8 (5.6%)|
|Upper respiratory infection||5 (5.3%)||3 (3.2%)||2 (4.0%)||5 (3.5%)|
|Abnormal dreams||5 (5.3%)||1 (1.1%)||1 (2.0%)||2 (1.4%)|
|Weight increased||5 (5.3%)||1 (1.1%)||1 (2.0%)||2 (1.4%)|